• but chylomicrons will be absent in serum after 8 to 12 hours fasting.
• (i.e this is why incomplete fasting will show high TGL).

[!INFO] The strongest index of CVD risk is "non HDL cholesterol".
This is reported by the lab as the Total cholesterol - HDL cholesterol

Lipid transport in the blood

#2021BSQ-JUL Q34
So mitochondrial disorders could be caused by defects in mitochondrial DNA or defects in nuclear DNA. (but these "mitochondrial diseases" don't show "mitochondrial inheritance")

"the CEO of Pearson kissed Leia while MELAS, MERRF and NARP Looked-ON"

• CPEO, Pearson Xn, KSS , Leigh Xn, NARP, MELAS, MERRF, LHON
  

Leber hereditary optic neuropathy

• maternally inherited bilateral subacute optic neuropathy
• LHON typically produces severe and permanent visual loss
• Predominantly affects males (85%)
• onset : late teens.

[!TIP] Mnemonic: Affects, eyes, ears, brain, heart and movement -everything you need for sports ;)

#2021BSQ-JUL Q25

• parasympathetic:
  • causes constriction - miosis; begins at the Edinger-Westphal nucleus near the occulomotor nerve nucleus. The fibers enter the orbit with CNIII nerve fibers and ultimately synapse at the cilliary ganglion.
• sympathetic:
  - Don't confuse this sympathetic innervation with innervation of the superior tarsal (Muller's muscle) for which sympathetic fibres travel with the superior division of the oculomotor nerve. (but in Horner's syndrome, both are affected anyway)

[!INFO] The ciliary ganglion an it's associated nerves are important in understanding the autonomic innervation of the eye :

Short ciliary nerves contains sympathetic and parasympathetic nerves.
Long ciliary nerves only contain sympathetic (but also sensory) fibers.

2. Muller's muscle (Superior tarsal muscle) - contributes to 1 - 2 mm of eye lid retration; innervated by the sympathetic system.

Source

Immune system

Components of the innate immune system:

• Musocal barriers
• Marcophages
• Neutrophils
• Complement system
• Natural killer cells

Macrophage function

Macrophages function as

1. Mediators of inflammation (see diagram below)
2. Effectors of the immune response

Inflammatory role:

In addition to phagocytic and microbicidal actions, macrophages secrete cytokines which stimulate repair and sustain inflammation.

Effector role:
Macrophages function as effectors of adaptive immunity

• Effectors of humoral immunity: Phagocytosing microbes coated with antibodies or complement
• Effectors of cell mediated immunity: Macrophages are the most important phagocytes in the cell-mediated arm of adaptive immune responses. Macrophages respond to T helper cell signals which increase their killing ability, thereby functioning as effectors of cell mediated immunity.

Natural killer cells

NK cells are lymphocytes but do no express antigen specific receptors like T or B cells.
Balance between inhibitory and activating stimulation decides whether the NK cell kills the target cell or not.

• MHC class I molecules are downregulated by a cell a in response to viral infections, other infections and stress.
• Activator receptor binding molecules are expressed on cells with DNA damage, stress or infections.

NK cells can destroy cells without previous sensitization.

Killing is mediated by cytotoxic molecules which are stored within secretory lysosomes, a specialized exocytic organelle found in NK cells - Source

Important in destroying tumour cells.
Tumour cells may downregulated MHC-class I molecules to avoid detection by T cells. But loss of MHC-class I will activate NK cells. Therefore, NK cells and T cells function in a complementary fashion to eliminate tumour cells.

Antigen presenting cells

The main type of antigen presenting cell is the dendritic cell.
Other cells are also involved.
Dentric cell type 1: Dentritic cells

• Present under epithelial surfaces and in interstitium to capture invading and circulating antigens, respectively.
• Have high levels of MHC-Class II and T cell costimulatory molecules.
• They capture and present antigens to T cells.
  
  Dendritic cell type 2: Follicular dentritic cells
• Located in germinal centers of lymphoid follicles in the spleen and lymph nodes.
• They have recetors for Fc porition of IgG and complement proteins.
• Therefore, effectively bind opsonized antigens.
• They display antigens to activated B cells for secondary antibody responses. They don't stimulate T cells.

Macrophages and B cells can also act as antigen presenting cells.

Ataxia telangiectasia

#autosomal-Recessive

There is a mutation in the ATM gene.

[!INFO] This gene is necessary for the action of tumour suppressors p53 and BRCA1.

One manifestation of the disease is increased susceptibility to malignancies.

• Classic AT usually presents either at birth, with partial combined immunodeficiency, or in early childhood, when neurologic abnormalities begin.
• Young children develop progressive cerebellar ataxia, abnormal eye movements, extrapyramidal motor dysfunction, and oculocutaneous telangiectasias.
• Progressive pulmonary disease and hematologic malignancy are major causes of morbidity and mortality
• Immunodeficiency (there is reduced number of T cells) is most commonly manifested by recurrent sinopulmonary infections.

Tumour markers

#2021BSQ-JUL Q31

3. Alpha-fetoprotein (AFP) - Liver cancer, germ cell tumors, particularly testicular cancer
4. Neuron-Specific Enolase (NSE) - Neuroendocrine tumors, small cell lung cancer
5. Epidermal Growth Factor Receptor (EGFR) - Non-small cell lung cancer, colorectal cancer

\Large{RR=\frac{risk\ of\ event\ in\ one\ group}{risk\ of\ event\ in\ other\ group}}
If the exposure lowers the risk of an outcome, then the relative risk will be less than 1. Source

\Large{OR=\frac{odds\ of\ event\ in\ one\ group}{odds\ of\ event\ in\ other\ group}}
In retrospective studies (case-control) studies, the total number of people "at risk" is not available. RR cannot be calculated. OR must be used.
Source

To determine "Whether the observed effect of an intervention is clinically important",
we use
$$
\Large{ARR = Risk\ in\ Control\ group - Risk\ in\ intervention\ group}
$$

In the above example, the baseline risk of death was 44% and ligation, with an ARR of 16% reduced this risk to 28%, which is nearly two-third (=0.28/0.44 = 0.636 or 64%) of the baseline risk. This is a medium-sized “relative” effect. However, if the baseline risk of death had been 20%, then a 16% ARR would bring the risk down to 4%, i.e. to about one-fifth of the original risk, a much bigger change in relative terms
\Large{RRR = \frac{ARR}{risk\ in\ \mathbf{control}\ group}}

Attributable risk

$$
\Large{Attributble\ Risk = Risk\ in\ Exposed - Risk\ in\ Unexposed}
$$

Source

Hypothesis testing

Types of tests

ANOVA

[!INFO] The basic principle of ANOVA

Which variance (between the groups of within the groups) accounts for most of the variation seen in the population?

Tests the hypothesis that the means of two or more populations are equal.
There are different types of ANOVA:

• This is one: "One way ANOVA = single factor ANOVA = without repetition of measurements. "

One way ANOVA is an extension of the t-test for independent samples to more than two groups. (i.e at least 3 independent samples).

If there are more than two dependent samples, we must use the ANOVA with repeated measurements.

ANOVA asks "Is there a difference in the population between the different groups (classified by the independent variable) with respect to the dependent variable".
I.e is there a difference in ages between groups using different statistics packages?

It does not give any information about the direction of the relationship.

Example

Is there a difference in age between users who use different statistic packages?

[!INFO] What is the null hypothesis for an ANOVA (one way)?
The null hypothesis is "there are no differences between the means of the individual groups".
The alternative is "there is a difference between at least two of the groups.

ANOVA compares a categorical variable to a continuous variable.

How much of the variation in the mean between the groups is explained by division of the population into the selected groups?

The result of an ANOVA test will be an F statistic.
The ANOVA test has two degree of freedom parameters based on the samples per group and number of groups.
The critical F value for a given combination of any two degree-of-freedom parameters can be looked up from a table.
An F value above the critical F value will disprove the null hypothesis. Source

Mann-Whitney U test

AKA - Wilcoxon rank sum test

This test can be extended to test more than two groups; That test is called the Kruskal Wallis test.

Source<- good video!
Source <- another worked example

It is a non-parametric test that is used to compare two sample means that come from the same population, and used to test whether two sample means are equal or not. Usually, the Mann-Whitney U test is used when the data is ordinal or when the assumptions of the t-test are not met. Source

The Mann-Whitney U test is used to compare differences between two independent groups when the dependent variable is either ordinal or continuous, but not normally distributed.

Assumptions of the Mann-Whitney U test:

1. The sample drawn from the population is random.
2. Independence within the samples and mutual independence is assumed.  That means that an observation is in one group or the other (it cannot be in both).
3. Ordinal or (continuous) measurement scale is assumed.

Similar application to a independent sample T test.
The test is performed to compare two samples to equivalence.

However, Mann-Whitney U test can be used when the T test is unsuitable due to

1. Non - normally distributed data
2. Sample size is too small.

It is a 'rank based' test.

Null hypothesis : no difference between the ranks of each treatment.

To perform a Mann-Whitney U test:

1. Each value is given a rank (ranks range from 1 to n where n is the total number of samples in both samples).
2. Values are arranged in ascending order so that each value will be given a rank.
   1. One rank can have only one value.
   2. Therfore, duplicate values will occupy one or more adjacent tanks.
3. Then, go back to the samples and add up the ranks assigned for each data point in the sample.
4. This gives a total rank score for each sample.
5. Using this total rank score, we calculate a "U statistic" for each sample.
6. Select the lowest U statistic among the two groups.
7. Look up the critical U value from tables. A U table shows the critical U value any combination of sample sizes. (realistically from 1 to 20)
8. To reject the null hypothesis, the obtained U valued has to be less than or equal the critical U value. (this is different that most other hypothesis tests)

Variance

$$
Sample\ variance = s^2 = \frac{Sum\ of\ Differences\ of\ Squares}{Degrees of freedom}=\frac{\Sigma (x-\bar{x})^2}{n-1}
$$
"Sample variance" here actually means "estimate of the population variance" based on the variance of the sample that we have. Hence, the sum of differences is divided by n-1 and not n. (where n = sample size).

CREST syndrome

The acronym "CREST" refers to the five main features: calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia.
Raynaud's phenomenon can precede the others by a long time. Source

- Beak like nose and microstomia
- telangiectasiaa and dilated nail fold capillary loops. 

Diagnosis

• ANA is positive in 95%.
• Anti-centromere (ACA) -> associated with limited cutaneous type.

• [!TIP] C for centromere and cutaneous

• Anti-topoisomerase -> Associated with Diffuse cutaneous type.

Caused by #autosomal-Recessive defect in ATP7B gene on Chromosome 13 which affects a copper transporting ATPase.
No male / female predominance.